Objective: Define polydatin’s therapeutic mechanism targeting astrocyte-mediated neuroinflammation in Parkinson’s disease (PD) and assess combinatorial efficacy with dopamine progenitor transplantation.

Background: PD progression involves substantia nigra dopaminergic neuron degeneration exacerbated by astrocyte-driven neuroinflammation. Current therapies lack disease-modifying capacity. Polydatin, a natural stilbenoid, shows neuroprotection but requires mechanistic validation in PD pathophysiology.

Method: Network pharmacology (CTD/TargetNet/SwissTargetPrediction/ChEMBL) identified polydatin targets. PD-associated genes from GSE7621 (9 controls/17 PD) were filtered via DESeq2/WGCNA. Molecular docking (AutoDock Vina) confirmed target interactions. Integration of substantia nigra single-cell sequencing data (GSE184950) via Seurat clustering and cell-type enrichment analysis localized DRD2 specificity to astrocytes. In vitro, Lentiviral DRD2-KO astrocytes ± polydatin underwent RNA-seq/KEGG pathway analysis. Astrocyte-specific DRD2-cKO mice with MPTP-induced PD received polydatin; outcomes were assessed via WB (CRYAB/NF-κB), ELISA (IL-1β/IL-6/TNF-α), and TH+ neuron counts. Engineered TH+/FOXA2+ progenitors were transplanted into AAV-GFAP-Cre-mediated DRD2-KO PD rats, evaluating graft survival and neuroinflammation.

Results: Network pharmacology prioritized DRD2 (-7.61 kcal/mol) among 404 polydatin targets. Single-cell analysis revealed DRD2 enrichment in activated astrocytes (GFAP+/S100β+) from PD patients (p<0.01). Mechanistically, polydatin suppressed NF-κB phosphorylation and upregulated CRYAB via DRD2 activation, effects abolished upon DRD2 knockout. In vivo, polydatin increased dopaminergic neuron survival by 55% (TH+ cells, p<0.01) and reduced IL-1β/IL-6/TNF-α by 70% (p<0.001). Co-transplantation boosted graft survival 2.2-fold (p<0.01) while attenuating astrogliosis and microglial infiltration, demonstrating dual efficacy via CRYAB/NF-κB inhibition.

Conclusion: This study establishes polydatin’s neuroprotection via astrocytic DRD2/CRYAB/NF-κB axis modulation and demonstrates synergistic efficacy with cell replacement therapy, proposing a novel dual-target strategy for PD modification.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/unveiling-the-molecular-mechanism-of-polydatin-in-ameliorating-parkinsons-disease-via-the-drd2-cryab-nf-%ce%bab-axis-in-astrocytes-and-exploring-cell-therapy-strategies/